ROLE OF NONENZYMATICALLY GENERATED PROSTANOID, 8-ISO-PGF(2-ALPHA), IN PULMONARY OXYGEN-TOXICITY

Oxygen delivery at higher than ambient concentrations is in frequent clinical use, yet prolonged exposure can produce pulmonary edema in humans and animals. The specific mediators of oxygen toxicity are unknown, although evidence suggests that oxygen-based radicals such as superoxide anion contribute to this injury. Recently, 8-iso-prostaglandin F2 alpha (PGF(2 alpha)), an F-2-isoprostane formed by free radical-initiated lipid peroxidation of arachidonic acid, has been implicated in pulmonary injury. Nitric oxide (NO) also contributes to tissue oxygen radical load, and although believed to be beneficial, its metabolites may play a pathophysiological role by participating in lipid peroxidation and isoprostane formation. We hypothesized that 8-iso-PGF(2 alpha) and NO levels increase in high oxygen concentrations and that 8-iso-PGF(2 alpha) is associated with lung injury and accumulation of plasma albumin in pulmonary extravascular space. Levels of 8-iso-PGF(2 alpha) in bronchial alveolar lavage fluid (BALF) of rats exposed to 90% O-2 at 1 atmosphere for 48 h (56 +/- 3 pg/ml) or 60 h (70 +/- 5 pg/ml) were significantly increased compared with levels in ambient air-exposed control rats (36 +/- 5 pg/ml). NO levels in BALF of rats exposed to 90% O-2 at 1 atmosphere for 60 h were increased 50% compared with NO levels in BALF of rats exposed to ambient air or 48 h of 90% O-2 (P < 0.05). Accumulation of radiolabeled plasma albumin in lung parenchyma of rats inhaling andiso-PGF(2 alpha) was also examined. The ratio of lung-associated radioactivity per gram of tissue to blood-associated radioactivity was increased 90% in 8-iso-PGF(2 alpha)-exposed group compared with vehicle group (P < 0.01). This study provides evidence that hyperoxia induces pulmonary formation of a nonenzymatically derived prostanoid that may be involved in pulmonary oxygen toxicity.